Project Summary The treatment of patients with high-grade gliomas remains a major medical problem. Transcranial MR guided focused ultrasound (MRgFUS) is a unique technology for noninvasive focal therapy in the brain. When enhanced by microbubbles, FUS can promote the transient opening of the blood brain barrier (BBB) to improve drug delivery in brain tumors. This technique can lead to more than 4-fold increase in the delivery and penetration of a range of anticancer agents, including small molecular weight chemotherapeutics. Recent clinical trials have confirmed the increased BBB permeability observed in preclinical models, demonstrated its safety, and provided evidence of its efficacy. Despite these promising findings, the number of under-treated (i.e. moderate to low BBB opening) and over-treated (i.e. MR-evident tissue damage) patients with FUS is above 40%, highlighting the challenges for translation and the need for new methods and technologies for guiding this minimally invasive intervention. An outstanding question in the field is how to map and control in the 3D space the microbubble dynamics that mediate the BBB permeabilization but cannot be detected by MRI. This proposal aims to establish novel closed-loop methods based on spectrally resolved passive acoustic imaging for mapping and controlling the cerebrovascular microbubble dynamics through human skull. Moreover, by engineering an innovative receiver array technology with high sensitivity, wide bandwidth, and adaptive active surface, this proposal will provide the required signal-to-noise ratio (SNR) and directivity to detect the weak acoustic emissions generated by the FUS excited microbubbles through human skull and throughout the brain. This array, which is amenable to the proposed closed-loop methods, will be integrated to an MRgFUS phased array and used to characterize the type and strength of microbubble vibration through human skull, expand the treatment window to theoretical limits (i.e. single microbubble detection) and provide the ability to locally define and refine the exposure settings during FUS interventions. In addition to optimum exposure settings for safe and robust BBB opening, longitudinal assessment and quantification of the FUS-meditated changes in BBB permeability is crucial for identifying tumor and drug-specific treatment windows. By recognizing that the transport across the BBB is bidirectional, it is hypothesized that cancer soluble molecules can provide a simple, yet safe and effective method to longitudinally assess the FUS-mediated changes to the BBB permeability and enable monitoring the response to therapy. Thus, by integrating bioanalytical and computational methods, this proposal seeks to establish a minimally invasive assay to guide FUS-interventions in the brain. If successful, the proposed methods, technology, and findings, which will be tested in models of glioblastoma with a small molecular weight chemotherapeutic agent and under clinically relevant conditions, will not only enable the delivery of tumor killing molecules to high-grade gliomas but also facilitate the successful translation this potentially transformative FUS intervention to the clinics.